Human papillomaviruses (HPVs) are small DNA viruses that infect various epithelial tissues. A subset of anogenital HPVs, the 'high risk' HPVs including HPV-16 and 18 genotypes, are associated with nearly all cervical carcinomas, as well as the majority of other anogenital cancers and a subset of head and neck cancers. Each year in the US, over 30,000 new cancers arise from high-risk HPV infections. Current regimens for treating these cancers rely on decades old strategies. Five-year survival rates for advanced grade cancers remain low. A recently FDA-approved HPV vaccine holds promise in preventing new infections, but it will not have an impact on cancer incidence until 2040 and beyond. Therefore there remains an urgent need to develop improved means for treating and/or preventing HPV-associated cancers and thereby increase survival rates and decrease suffering among those afflicted. The goal of this MMHCC application is to identify new, more effective regimens for treating and preventing HPV-positive cancers. We will make use of genetically engineered mouse strains that express the HPV16 E6 and E7 oncogenes in relevant tissues as the preclinical model in which to pursue these goals. These mice have been used to establish well-validated models for HPV associated cervical cancer and head and neck cancers. Three major goals will be pursued: 1) investigate the use of anti-estrogens in the treatment and prevention of cervical cancer, 2) validate kinase targets for therapy of HPV associated premalignant lesions and cancer, and 3) develop effective immunotherapies against HPV-associated cancers.